Bruns P Ellerbroek T de Jong K Tesselaar A Stam M Salgado G Hutter L Brosens M Kwon J Diez Martin J Boelens J MartinezPicado ID: 913759
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Slide1
A.
M.J. Wensing , K. Bosman , A. Bruns , P. Ellerbroek , T. de Jong , K. Tesselaar , A. Stam , M. Salgado , G. Hutter , L. Brosens , M. Kwon , J. Diez Martin , J. Boelens , J. Martinez-Picado , J. Kuball and M. Nijhuis on behalf of the IciStem consortiumAIDS2018
Dominant HIV DNA populations present in different T-cell subsets before stem cell transplantation
persist in tissues early after transplantation with CCR5Δ32 stem cells
Slide2Disclosure
Relations that could be relevant for the meetingCompany namesSponsorship or refund fundsINVESTIGATOR INITIATED RESEARCH GRANTS*UNRESTRICTED EDUCATIONAL GRANTS*Janssen, Viiv Healthcare, Merck, Gilead
Payment or other financial remunerationCONSULTANCY FEES*
Gilead,
Viiv
Healthcare,
Janssen, Merck
Shareholder rights
None
Others: CONFERENCE TRAVELING/MASTERCLASS
FEE
*
Virology Education
* All paid to my institution
Slide3HIV-infected persons have a higher risk for
hematological malignacies, such as AML, MDS and lymphomaThere is a lower overall survival rate after stem cell transplantation (SCT) for these conditions as compared to a matched control group of HIV negative patients
Timothy Brown, the
so called Berlin patient
was
cured from both AML and HIV-infection after
SCT
Sutton et al. Br J Hematol 2001; Hutter et al. aids Res Ther 2016; Kaner et al. Blood 2016; aboulafia et al. aids 2002; Ryu Intern Med 2001
HIV
and
stem
cell
transplantation
Slide4CCR5
Δ32Δ32 donor cells1Absence of viruses able to use other co-receptors (i.e. CXCR4 tropic-virus)2Immune suppressive treatment (i.e. ATG levels)
Total body irradiationGraft Versus Host DiseasePatient’s own CCR5 heterozygous state (smaller HIV-DNA reservoir
?)
1Hutter et al, NEJM, 2008; 2Symons et al, CID, 2014
-Which factors contributed to the cure?
Slide5Essen patient: SCT with CCR5𝚫32/𝚫32 donor cells1Minnesota Patient
: SCT with CCR5𝚫32/𝚫32 donor cells2 Successful engraftment,
patient died from GVHD at day 73
HIV DNA detected
in
tissues post-transplant
Boston Patients: transplanted with CCR5WT donor cells3- Successful engraftment, GVHD- No HIV detected in blood and rectal mucosa
- ATI: Viral rebound was observed after 12, 32 weeksIt is unknown which reservoirs fueled the viral rebound-1. Kordelas et al, NEJM, 2014, 2. Rottenberher et al. Open Forum
Inf
Dis 2017, 3.
Henrich
et al, Ann. Intern. Med., 2014
HIV
and
stem
cell
transplantation
Slide6IciStem
Consortium:Stem cell transplantation (CCR5Δ32/Δ32 or CCR5WT/WT)International collaboration to guide and investigate the potential for HIV cure in HIV-infected patients requiring allogeneic stem cell transplantation for hematological disorders
AIM 1To guide clinicians involved in allogeneic SCT procedures in HIV infected individuals
AIM 2
To better understand the underlying biological processes leading to viral reservoir reduction and potential cases of HIV-1 eradication/remission.
www.icistem.org
Principal Investigators:
Javier Martinez
PicadoAnnemarie Wensing
Slide737 patients registered from 9 different
countries30 patients transplantedMean follow-up: 887 days 12 patients deceased after SCT (Δ32/Δ32)12 patients beyond 2nd year post-SCTOverview of registration
Slide8The viral reservoir
Slide9Phenotypic and genotypic coreceptor tropism analysis, HIV
reservoir quantification using ddPCR and viral characterization using deep-sequencing of PBMCs, CD4 -T-cell subsets (Tn, Tcm, Ttm, Teff) and bonemarrow,Single copy assay (SCA) on plasma. Post-SCT viral dynamics were analyzed using ddPCR and SCA. The post-mortem viral reservoir was quantified using ddPCR and characterized by deep-sequencing.Methods
Slide10Viral load
(copies/mL plasma)TreatmentPatient #5
Slide11Patient
HIV Diagnosis
Start of ART
Indication of SCT
Date of transplant
Stem cell therapy
CCR5 genotype stem cells
cART cessation
#5 Utrecht
1998
1998
Myelodysplastic
syndrome
(MDS)
May 2012
Cord
blood
transplant+3
rd
party donor
CCR5
Δ
32
/
Δ
32
No
Patient #5
Slide120
2
4
12
10
8
6
14
100
200
300
600
500
400
Weeks
-3
-2
-1
0
1
2
3
4
5
6
7
8
9
10
16
1000
700
800
900
a n t i r e t r o v i r a l t h e r a p y
Donor engraftment
Subtype B
FPR
88.4%
CCR5-tropic virus
SCT
(
CCR5
Δ
32/
Δ
32)
HIV RNA in plasma (Single copy Assay, copies/mL)
CD4 count (cells/µL)
Proviral
DNA (copies/million PBMCs)
100
%
Death
Patient 5: FPR of pre-SCT proviral DNA
Patient #5
Slide13Patient #5
Slide14After SCT, a sharp decline in HIV DNA is observed to below level of detection.
In Patient #5 in the neutropenic phase early post-SCT, HIV-DNA could no longer be detected in PBMCs. In contrast, dominant HIV-DNA populations persisted in tissues indicating that tissue reservoirs may play an important role as long-standing viral reservoirs.Sequences of virus obtained from post-mortem biopsies don’t indicate compartmentalization or viral evolution.
Conclusions
Slide15A number of surviving patients
of the consortium with longer follow up > 2 years after SCT have undetectable viral load and undetectable DNA concentrations in blood and in isolated T-cells from other tissues
Future directions
Slide16IciStem
researchers & project management
María Salgado, Judith
Dalmau
(AIDS Research Institute IrsiCaixa, Barcelona),
Arjen
Stam, Kobus Bosman, Antoinet van Kessel
(University Medical Center Utrecht), Pascual Balsalobre Lopez (Hospital Gregorio Marañón, Madrid), Johanna Eberhard (UMC Hamburg-
Eppendorf)
Scientific
Advisors
:
Koen van
Besien
, Jan
van Lunzen
IciStem
participants
Belgium:
Linos
Vandekerckhove
, Marie-
Angélique
de
Scheerder
, Eva Steel (University of Ghent)
Canada:
Lisa Barrett, Sharon
Oldford
, Nate
Stepner
, Marina Turner (NSHA/Dalhousie
University, Halifax)
Germany:
Dieter
Häussinger
, Guido
Kobbe
,
Björn
Jensen (University Hospital Düsseldorf
), Rolf Kaiser, Elena Knops (University of Cologne)Italy: Alessandra Bandera, Antonio Muscatello and Dr. Alessandro Soria (San Gerardo Hospital, Monza, Italy).Netherlands: Pauline Ellerbroek, Lodewijk Brosens, Anke Bruns, Erik van Maarseveen (UMC Utrecht) Jan van der Meer, Sacha Zeerleder (AMC)Spain: Ildefonso Espigado (University Hospital Virgen del Rocío, Seville)United Kingdom: Kavita Raj, Fabio Cruciani, Varun Mehra, Carmel Rice, (Kings College Hospital, London) Angela Bailey (Imperial College Healthcare NHS Trust, London)Waseem Qasim (Institute of Child Health & Great Ormond Street Hospital, London), Ravi Gupta (University College London AcknowledgementsThe IciStem consortiumJavier Martinez-Picado (Co-PI, Virologist, AIDS Research Institute IrsiCaixa, Barcelona)Annemarie Wensing (Co-PI, Clinical Virologist, University Medical Center Utrecht) Jose L. Díez Martin (Hematologist, Hospital Gregorio Marañón, Madrid)Mi Kwon (Hematologist, Hospital Gregorio Marañón, Madrid)Gero Hütter (Hematologist, Cellex Dresden) Jürgen Kuball (Hematologist, University Medical Center Utrecht) Monique Nijhuis (Virologist, University Medical Center Utrecht) Vanderson Rocha (Hematologist Cord Blood Bank Specialist Oxford University)Asier Sáez-Cirión (Immunologist,Pasteur Institute, Paris) Julian Schulze zur Wiesch (Infectious disease specialist, UMC Hamburg-Eppendorf)
Slide17Acknowledgement
Translational Virology, UMCU